Viral infections can activate the HPA axis, presumably by releasing cytokines which then increase hypothalamic CRF secretion. Our pilot data provide evidence that HIV infection increases basal cortisol secretion even in early asymptomatic stages prior to the onset of HIV-induced immuno- suppression. Therefore, we hypothesize that HIV will result in glucocorticoid hypersecretion by stimulating hypothalamic CRF release and disinhibiting the HPA axis at limbic receptor sites. Since we have found diminished secretion of the adrenal androgen DHEA in our HIV+ hypercortisolemic HNRC subjects, we also hypothesize that the neurotoxic and immunosuppressive effects of glucocorticoids will be less opposed by DHEA (which possesses antiglucocorticoid and neuroprotective properties) during HIV infection. We therefore expect HIV-induced HPA abnormalities will have an important role in the development of neurocognitive impairment, structural brain defects, mood dysregulation, and impaired adaptation to psychosocial stress during HIV infection. We will first determine the specific abnormalities at each level of the HPA axis which are caused by HIV infection and define the time course for the longitudinal changes in HPA axis secretion from early asymptomatic stages to AIDS. Basal HPA secretion will be measured at 20-minute intervals over a 3-hour afternoon period which provides an accurate index of the mean 24-hour secretion pattern. We will then assess pituitary corticotroph sensitivity (with a 1 ug/kg CRF challenge) and limbic sensitivity to GC negative feedback (using a corticosterone suppression test). We will study cross- sectionally 4 groups of HIV+ subjects, selected to sample potentially discrete stagepoints in evolution of cellular immune decline. These HIV+groups (N=30 each) will be (1) 1993 CDC A1; (2)A2 with CD4lesser300 and A3; (3) CDC B2-B3; (4) CDC C2-C3. A fifth comparison group of 30 HIV- will also be examined. We will also perform a longitudinal study whereby we will assess at yearly intervals the HPA axis in HIV+ axis in HIV+A patients with intact (more500) and low(lesser300) levels of CD4. We hypothesize that basal hypercortisolism, DHEA depletion, decreased ACTH responses to CRF, and loss of GC negative feedback will be significantly correlated with a high level of CNS infection by HIV, increasing cognitive impairment, MRI defects in limbic brain, and neurobehavioral disorders (i.e., mood dysregulation). We also predict that the magnitude of basal hypercortisolism in the presence of DHEA hyposecretion will be correlated with decreasing cellular immunity and highly predictive of immunologic progression to AIDS. A final specific aim will examine the effect of HIV infection on brain serotonin based on our pilot data revealing diminished HPA responses to fenfluramine in HIV+ patients. We hypothesize that HIV will alter serotonin release at hypothalamic CRF neurons resulting in neuroendocrine dysregulation and neurobehavioral disorders (i.e., depression).